QT PRODACT: A Multi-site Study of In Vitro Action Potential Assays on 21 Compounds in Isolated Guinea-Pig Papillary Muscles

Seiji Hayashi; Yoshihide Kii; Mitsuyasu Tabo; Hitoshi Fukuda; Tetsuji Itoh; Takashi Shimosato; Hideto Amano; Mamoru Saito; Hajime Morimoto; Kiyoshi Yamada; Atsuhiro Kanda; Toshimasa Ishitsuka; Takanobu Yamazaki; Yoichi Kiuchi; Shinya Taniguchi; Tatsuya Mori; Shigekazu Shimizu; Yuji Tsurubuchi; Shun-ichi Yasuda; Shin-ichi Kitani; Chiaki Shimada; Kazuo Kobayashi; Masaharu Komeno; Chieko Kasai; Toshiyasu Hombo; Keiji Yamamoto

doi:10.1254/jphs.QT-A1

Full Papers

QT PRODACT: A Multi-site Study of In Vitro Action Potential Assays on 21 Compounds in Isolated Guinea-Pig Papillary Muscles

Seiji Hayashi, Yoshihide Kii, Mitsuyasu Tabo, Hitoshi Fukuda, Tetsuji Itoh, Takashi Shimosato, Hideto Amano, Mamoru Saito, Hajime Morimoto, Kiyoshi Yamada, Atsuhiro Kanda, Toshimasa Ishitsuka, Takanobu Yamazaki, Yoichi Kiuchi, Shinya Taniguchi, Tatsuya Mori, Shigekazu Shimizu, Yuji Tsurubuchi, Shun-ichi Yasuda, Shin-ichi Kitani, Chiaki Shimada, Kazuo Kobayashi, Masaharu Komeno, Chieko Kasai, Toshiyasu Hombo, Keiji Yamamoto

Author information

Seiji Hayashi
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Discovery Research Laboratories, Nippon Shinyaku Co., Ltd., Japan
Yoshihide Kii
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Safety Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Japan
Mitsuyasu Tabo
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Safety Assessment Department, Chugai Pharmaceutical Co., Ltd., Japan
Hitoshi Fukuda
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Research Laboratories, Toyama Chemical Co., Ltd., Japan
Tetsuji Itoh
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Developmental Research Laboratories, Shionogi & Co., Ltd., Japan
Takashi Shimosato
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Research Department, NISSEI BILIS Co., Ltd., Japan
Hideto Amano
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., Japan
Mamoru Saito
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Drug Safety Research Laboratories, Eisai Co., Ltd., Japan
Hajime Morimoto
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Tokushima Research Institute, Otsuka Pharmaceutical Co., Ltd., Japan
Kiyoshi Yamada
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Pharmaceutical Research Laboratories, Toray Industries, Inc., Japan
Atsuhiro Kanda
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Pharmacobioregulation Research Laboratory, Taiho Pharmaceutical Co., Ltd., Japan
Toshimasa Ishitsuka
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Toxicology Laboratory, Mitsubishi Pharma Corporation, Japan
Takanobu Yamazaki
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Research Center, Kyorin Pharmaceutical Co., Ltd., Japan
Yoichi Kiuchi
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Medicinal Development Research Laboratories, Taisho Pharmaceutical Co., Ltd., Japan
Shinya Taniguchi
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Pharmaceutical Research Laboratories, Ajinomoto Co., Inc., Japan
Tatsuya Mori
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Toxicological Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan
Shigekazu Shimizu
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Kobuchisawa Laboratories, Fuji Biomedix Co., Ltd., Japan
Yuji Tsurubuchi
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Pharmacological Research Laboratories, Drug Safety Testing Center Co., Ltd., Japan
Shun-ichi Yasuda
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Study Department, Nihon Bioresearch Inc., Japan
Shin-ichi Kitani
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Pharmacology & Toxicology Department, Ina Research, Inc., Japan
Chiaki Shimada
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Research and Development Center, Fuso Pharmaceutical Industries, Ltd., Japan
Kazuo Kobayashi
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Pharmacodynamics Research Laboratories, Sankyo Co., Ltd., Japan
Masaharu Komeno
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Fukui Safety Research Laboratories, Ono Pharmaceutical Co., Ltd., Japan
Chieko Kasai
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Drug Safety Research Laboratories, Astellas Pharma Inc., Japan
Toshiyasu Hombo
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Drug Safety Research Laboratories, Astellas Pharma Inc., Japan
Keiji Yamamoto
Japan Pharmaceutical Manufacturers Association (JPMA)/QT PRODACT, Japan
Development Research Center, Takeda Pharmaceutical Co., Ltd., Japan

Keywords: action potential duration (APD) at 90% repolarization (APD₉₀), APD_30–90, triangulation, safety pharmacology, QT PRODACT

JOURNAL FREE ACCESS
Supplementary material

2005 Volume 99 Issue 5 Pages 423-437

DOI https://doi.org/10.1254/jphs.QT-A1

Details

Abstract

To construct a non-clinical database for drug-induced QT interval prolongation, the electrophysiological effects of 11 positive and 10 negative compounds on action potentials (AP) in guinea-pig papillary muscles were investigated in a multi-site study according to a standard protocol. Compounds with a selective inhibitory effect on the rapidly activated delayed rectifier potassium current (I_Kr) prolonged action potential duration at 90% repolarization (APD₉₀) in a concentration-dependent manner, those showing Ca²⁺ current (I_Ca) inhibition shortened APD₃₀, and those showing Na⁺ current (I_Na) inhibition decreased action potential amplitude (APA) and V_max. Some of the mixed ion-channel blockers showed a bell-shaped concentration-response curve for APD₉₀, probably due to their blockade of I_Na and/or I_Ca, sometimes leading to a false-negative result in the assay. In contrast, all positive compounds except for terfenadine and all negative compounds with I_Kr-blocking activity prolonged APD_30–90 regardless of their I_Na- and/or I_Ca-blocking activities, suggesting that APD_30–90 is a useful parameter for evaluating the I_Kr-blocking activity of test compounds. Furthermore, the assay is highly informative regarding the modulation of cardiac ion channels by test compounds. Therefore, when APD₉₀ and APD_30–90 are both measured, the action potential assay can be considered a useful method for assessing the risk of QT interval prolongation in humans in non-clinical safety pharmacology studies.
Supplementary material (Appendix): available only at http://dx.doi.org/10.1254/jphs.QT-A1

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